Effects of cariprazine, a novel antipsychotic, on cognitive deficit and negative symptoms in a rodent model of schizophrenia symptomatology

Abstract

Negative symptoms and cognitive impairment associated with schizophrenia are strongly associated with poor functional outcome and reduced quality of life and remain an unmet clinical need. Cariprazine is a dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors, recently approved by the FDA for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The aim of this study is to evaluate effects of cariprazine in an animal model of cognitive deficit and negative symptoms of schizophrenia. Following sub-chronic PCP administration (2mg/kg, IP for 7 days followed by 7 days drug-free), female Lister Hooded rats were administered cariprazine (0.05, 0.1, or 0.25mg/kg, PO) or risperidone (0.16 or 0.1mg/kg, IP) before testing in novel object recognition (NOR), reversal learning (RL), and social interaction (SI) paradigms. As we have consistently demonstrated, sub-chronic PCP significantly impaired behavior in these tests. Deficits were significantly improved by cariprazine, in a dose dependent manner in the operant RL test with efficacy at lower doses in the NOR and SI tests. Locomotor activity was reduced at the highest doses of 0.1mg/kg and 0.25mg/kg in NOR and SI. Risperidone also reversed the PCP-induced deficit in all tests. In conclusion, cariprazine was effective to overcome PCP-induced deficits in cognition and social behavior in a thoroughly validated rat model in tests representing specific symptom domains in schizophrenia patients. These findings support very recent results showing efficacy of cariprazine in the treatment of negative symptoms in schizophrenia patients.

A-582941, cholinergic alpha 7 nicotinic receptor agonist, improved cognitive and negative symptoms of the sub-chronic MK-801 model of schizophrenia in rats

“…Social behaviours of each rat were evaluated separately. The spending time for sniffing, climbing, and following behaviours was scored as an indicator of socialization and the spending time for avoiding was scored as an indicator of social withdrawal [23].…”

Agmatine-attenuated cognitive and social deficits in subchronic MK-801 model of schizophrenia in rats

“…All experiments were recorded with a camera. Spending time for sniffing, climbing, and following behaviours was measured as an indicator of socialization and spending time for avoiding was measured as an indicator of social withdrawal [33].…”

Current drug treatments targeting dopamine D3 receptor

“…Aripiprazole and cariprazine result equally active in reversing NOR deficits in rats given neonatal phencyclidine and housed in social isolation from weaning (Watson et al, 2016). Furthermore, both aripiprazole and cariprazine reverse subchronic phencyclidine-induced impairment in NOR in mice and rats (Nagai et al, 2009;Neill et al, 2016). However, unlike cariprazine, aripiprazole does not modify deficits in social behaviors in animals, corresponding to negative symptoms in schizophrenia (Watson et al, 2016).…”

“…More recently, cariprazine has been shown to revers impairment in both NOR and in social interaction induced in rat by phencyclidine (Neill et al, 2016;Watson et al, 2016); worthy of note, these effects occurred following a dose lower than those reducing locomotor activity (Neill et al, 2016). Cariprazine also attenuates the decrease in A C C E P T E D M A N U S C R I P T…”